Ibrutinib (IMBRUVICA™) is an orally administered drug that targets Bruton's tyrosine kinase (Btk). Btk is a member of the Tec tyrosine kinase family, which is expressed in most hematopoietic cells such as B cells. Btk plays a role in the development and activation of B cells. Mutations in the human Bkt gene cause the inherited disease X-linked agammaglobulinemia (XLA), with lack of peripheral B cells and low levels of serum Ig. In XLA, the primary immune deficit is B cell specific. Ibrutinib may be used for treating both B cell-related hematological cancers such as non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma.
The chemical name of ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one and it has the following chemical formula:

According to the Patient Leaflet of IMBRUVICA™, the drug's capsules for oral administration are supplied as white opaque capsules containing 140 mg ibrutinib as active pharmaceutical ingredient and excipients. The proposed dosing regimen of IMBRUVICA™ capsules is 560 mg (4×140 mg) once daily of ibrutinib to patients with Mantle Cell Lymphoma (MCL) or chronic lymphocytic leukemia (CLL).
International Patent Publication Number WO2013/184572 discloses crystalline forms including solvates of ibrutinib that are marked as Forms A, B, C, D, E and F. Also disclosed in Publication WO2013/184572 are pharmaceutical compositions that include ibrutinib, as well as methods of using it, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
The preparation of ibrutinib Form A is described in Routes 1-3 of example 1 of WO2013/184572. According to Route 1, an amorphous ibrutinib is dissolved or slurried in an organic solvent such as methyl tert-butyl ether or diisopropyl ether, or in a 10% aqueous mixture of an organic solvent such as acetone or isopropyl alcohol. The mixture is heated to 50° C. for one hour and then cooled to afford crystallization. According to Route 2, amorphous ibrutinib is mixed with water or with an aqueous mixture of isopropanol or with an organic solvent such as dioxane, toluene or anisole. Then, a sealed vial is placed in a maturation chamber cycling between 50° C. and ambient temperature for four hours each for five days to afford formation of solids. According to Route 3, ibrutinib is dissolved in methanol at 45° C. and water is added to form slurry, which is stirred at the elevated temperature for 3 hours. Then, the slurry is allowed to cool to ambient temperature and stirred for 16 hours followed by filtration to afford a solid. The solid is washed with a mixture of methanol and water and dried.
Application CN103694241 describes a new crystalline form of ibrutinib, which is denoted therein as “Form A”. The TGA presented in application CN103694241 may suggest that this form is a solvate of ibrutinib.
Ibrutinib is administered orally (560 mg/daily) to patients in order to obtain the desired therapeutic effect. The need for such a high dose of ibrutinib may be related to low bioavailability (the oral bioavailability of ibrutinib is reported to be 22.8% in rats) and in turn may be related to the adverse effects associated with the use of ibrutinib such as nausea or emesis, dizziness and diarrhea. Low bioavailability may be also related to variable absorption and potential variability of the desired therapeutic response.
There is a need for stable ibrutinib forms, which may be more soluble, and for processes for preparing such forms. The present invention provides such forms and processes for their preparation.